Trial Outcomes & Findings for Effect of Brivaracetam (BRV) on Nonpsychotic Behavioral Side Effects in Subjects Treated Previously With Levetiracetam (LEV) (NCT NCT01653262)

Results Overview

Nonpsychotic behavioral side effects include (but are not limited to) such symptoms as aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, irritability, etc. The Investigator completed the assessment by answering the following: "Has there been a clinically meaningful reduction of nonpsychotic behavioral side effects since the start of BRV?" \- Yes/No

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

29 participants

Primary outcome timeframe

From Study Entry (Visit1, Week -1) to the end of the Treatment Period (Visit 6, Week 12) or Early Discontinuation Visit

Results posted on

2018-07-11

Participant Flow

This study started to enroll subjects in July 2012. In Oct 2013, the Sponsor evaluated the study in light of the recruitment rate. Given the unanticipated lack of recruitment during the prior 8 weeks, a decision was made to stop recruitment as of 16 Oct 2013.

Participant Flow refers to the Enrolled Set. In total, 32 subjects were screened and 29 subjects were enrolled instead of 30 subjects as per protocol amendment 2. This difference was considered as insignificant and not affecting the planned analysis.

Participant milestones

Participant milestones
Measure	Brivaracetam The subjects will be treated with Brivaracetam (BRV) tablets 200 mg/day during 12 weeks: four 25 mg tablets, twice daily. Based on the Investigator's judgement, at any time, the dose can be decreased to BRV 150 mg/day, 100 mg/day, or 50 mg/day. Flexible dosing, can be up- and down-titrated as needed. At the end of the Treatment Period, the subject will either enter the N01372 long-term follow-up study or down-titrate during 4 weeks.
Overall Study STARTED	29
Overall Study COMPLETED	26
Overall Study NOT COMPLETED	3

Reasons for withdrawal

Reasons for withdrawal
Measure	Brivaracetam The subjects will be treated with Brivaracetam (BRV) tablets 200 mg/day during 12 weeks: four 25 mg tablets, twice daily. Based on the Investigator's judgement, at any time, the dose can be decreased to BRV 150 mg/day, 100 mg/day, or 50 mg/day. Flexible dosing, can be up- and down-titrated as needed. At the end of the Treatment Period, the subject will either enter the N01372 long-term follow-up study or down-titrate during 4 weeks.
Overall Study Lack of Efficacy	1
Overall Study SAE, non-fatal	1
Overall Study AE, non-serious non-fatal	1

Baseline Characteristics

Effect of Brivaracetam (BRV) on Nonpsychotic Behavioral Side Effects in Subjects Treated Previously With Levetiracetam (LEV)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Brivaracetam n=29 Participants The subjects will be treated with Brivaracetam (BRV) tablets 200 mg/day during 12 weeks: four 25 mg tablets, twice daily. Based on the Investigator's judgement, at any time, the dose can be decreased to BRV 150 mg/day, 100 mg/day, or 50 mg/day. Flexible dosing, can be up- and down-titrated as needed. At the end of the Treatment Period, the subject will either enter the N01372 long-term follow-up study or down-titrate during 4 weeks.
Age, Categorical <=18 years	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	29 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants
Age, Continuous	35.8 years STANDARD_DEVIATION 11.8 • n=5 Participants
Sex: Female, Male Female	14 Participants n=5 Participants
Sex: Female, Male Male	15 Participants n=5 Participants

PRIMARY outcome

Timeframe: From Study Entry (Visit1, Week -1) to the end of the Treatment Period (Visit 6, Week 12) or Early Discontinuation Visit

Population: The Full Analysis Set (FAS) consisted of all subjects who received at least 1 dose of Brivaracetam and had at least 1 post-Baseline evaluation of behavioral side effects.

Nonpsychotic behavioral side effects include (but are not limited to) such symptoms as aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, irritability, etc. The Investigator completed the assessment by answering the following: "Has there been a clinically meaningful reduction of nonpsychotic behavioral side effects since the start of BRV?" \- Yes/No

Outcome measures

Outcome measures
Measure	Brivaracetam n=29 Participants The subjects will be treated with Brivaracetam (BRV) tablets 200 mg/day during 12 weeks: four 25 mg tablets, twice daily. Based on the Investigator's judgement, at any time, the dose can be decreased to BRV 150 mg/day, 100 mg/day, or 50 mg/day. Flexible dosing, can be up- and down-titrated as needed. At the end of the Treatment Period, the subject will either enter the N01372 long-term follow-up study or down-titrate during 4 weeks.
Percentage of Subjects Who Achieved a Clinically Meaningful Reduction of Nonpsychotic Behavioral Side Effects Based on the Investigator's Overall Assessment From Study Entry to the End of the Treatment Period	93.1 percentage of subjects

SECONDARY outcome

Timeframe: From Baseline (maximum of 12 weeks prior to Study Entry at Week -1) to the end of the Treatment Period (Visit 6, Week 12) or Early Discontinuation Visit

Population: The Full Analysis Set (FAS) consisted of all subjects who received at least 1 dose of Brivaracetam and had at least 1 post-Baseline evaluation of behavioral side effects.

Nonpsychotic behavioral side effects include (but are not limited to) such symptoms as aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, irritability, etc.

Outcome measures

Outcome measures
Measure	Brivaracetam n=29 Participants The subjects will be treated with Brivaracetam (BRV) tablets 200 mg/day during 12 weeks: four 25 mg tablets, twice daily. Based on the Investigator's judgement, at any time, the dose can be decreased to BRV 150 mg/day, 100 mg/day, or 50 mg/day. Flexible dosing, can be up- and down-titrated as needed. At the end of the Treatment Period, the subject will either enter the N01372 long-term follow-up study or down-titrate during 4 weeks.
Shift in the Maximum Intensity From Baseline to the End of the Treatment Period for Side Effects Primarily Associated With Discontinuation of Levetiracetam (LEV) as Determined by the Investigator Improvement	8 subjects
Shift in the Maximum Intensity From Baseline to the End of the Treatment Period for Side Effects Primarily Associated With Discontinuation of Levetiracetam (LEV) as Determined by the Investigator Unchanged	2 subjects
Shift in the Maximum Intensity From Baseline to the End of the Treatment Period for Side Effects Primarily Associated With Discontinuation of Levetiracetam (LEV) as Determined by the Investigator Worsening	0 subjects
Shift in the Maximum Intensity From Baseline to the End of the Treatment Period for Side Effects Primarily Associated With Discontinuation of Levetiracetam (LEV) as Determined by the Investigator Resolved	19 subjects

SECONDARY outcome

Timeframe: From Study Entry (Visit1, Week -1) to the end of the Treatment Period (Visit 6, Week 12) or Early Discontinuation Visit

Population: The Full Analysis Set (FAS) consisted of all subjects who received at least 1 dose of Brivaracetam and had at least 1 post-Baseline evaluation of behavioral side effects.

There are seven levels for the I-GEBSE: * Marked improvement * Moderate improvement * Slight improvement * No change * Slight worsening * Moderate worsening * Marked worsening

Outcome measures

Outcome measures
Measure	Brivaracetam n=29 Participants The subjects will be treated with Brivaracetam (BRV) tablets 200 mg/day during 12 weeks: four 25 mg tablets, twice daily. Based on the Investigator's judgement, at any time, the dose can be decreased to BRV 150 mg/day, 100 mg/day, or 50 mg/day. Flexible dosing, can be up- and down-titrated as needed. At the end of the Treatment Period, the subject will either enter the N01372 long-term follow-up study or down-titrate during 4 weeks.
Change From Study Entry in Nonpsychotic Behavioral Side Effects to the End of the Treatment Period/Early Discontinuation Visit, Measured by Means of the Investigator Global Evaluation of Nonpsychotic Behavioral Side Effects (I-GEBSE) Scale Marked improvement	10 subjects
Change From Study Entry in Nonpsychotic Behavioral Side Effects to the End of the Treatment Period/Early Discontinuation Visit, Measured by Means of the Investigator Global Evaluation of Nonpsychotic Behavioral Side Effects (I-GEBSE) Scale Moderate improvement	10 subjects
Change From Study Entry in Nonpsychotic Behavioral Side Effects to the End of the Treatment Period/Early Discontinuation Visit, Measured by Means of the Investigator Global Evaluation of Nonpsychotic Behavioral Side Effects (I-GEBSE) Scale Slight improvement	4 subjects
Change From Study Entry in Nonpsychotic Behavioral Side Effects to the End of the Treatment Period/Early Discontinuation Visit, Measured by Means of the Investigator Global Evaluation of Nonpsychotic Behavioral Side Effects (I-GEBSE) Scale No change	2 subjects
Change From Study Entry in Nonpsychotic Behavioral Side Effects to the End of the Treatment Period/Early Discontinuation Visit, Measured by Means of the Investigator Global Evaluation of Nonpsychotic Behavioral Side Effects (I-GEBSE) Scale Slight worsening	1 subjects
Change From Study Entry in Nonpsychotic Behavioral Side Effects to the End of the Treatment Period/Early Discontinuation Visit, Measured by Means of the Investigator Global Evaluation of Nonpsychotic Behavioral Side Effects (I-GEBSE) Scale Moderate worsening	0 subjects
Change From Study Entry in Nonpsychotic Behavioral Side Effects to the End of the Treatment Period/Early Discontinuation Visit, Measured by Means of the Investigator Global Evaluation of Nonpsychotic Behavioral Side Effects (I-GEBSE) Scale Marked worsening	1 subjects
Change From Study Entry in Nonpsychotic Behavioral Side Effects to the End of the Treatment Period/Early Discontinuation Visit, Measured by Means of the Investigator Global Evaluation of Nonpsychotic Behavioral Side Effects (I-GEBSE) Scale Missing	1 subjects

SECONDARY outcome

Timeframe: From Baseline (maximum of 12 weeks prior to Study Entry at Week -1) to the end of the Treatment Period (Visit 6, Week 12) or Early Discontinuation Visit

Population: The Full Analysis Set (FAS) consisted of all subjects who received at least 1 dose of Brivaracetam and had at least 1 post-Baseline evaluation of behavioral side effects.

Nonpsychotic behavioral side effects include (but are not limited to) such symptoms as aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, irritability, etc.

Outcome measures

Outcome measures
Measure	Brivaracetam n=29 Participants The subjects will be treated with Brivaracetam (BRV) tablets 200 mg/day during 12 weeks: four 25 mg tablets, twice daily. Based on the Investigator's judgement, at any time, the dose can be decreased to BRV 150 mg/day, 100 mg/day, or 50 mg/day. Flexible dosing, can be up- and down-titrated as needed. At the end of the Treatment Period, the subject will either enter the N01372 long-term follow-up study or down-titrate during 4 weeks.
Number of Subjects Who Have a Complete Abatement of Nonpsychotic Behavioral Side Effects for the Last Assessment During the Treatment Period, Based on the Investigator's Overall Assessment	18 subjects

SECONDARY outcome

Timeframe: From Visit 2 (Week 0) to Visit 6 (Week 12)

Population: The Full Analysis Set (FAS) consisted of all subjects who received at least 1 dose of Brivaracetam and had at least 1 post-Baseline evaluation of behavioral side effects.

Nonpsychotic behavioral side effects (NBSE) include (but are not limited to) such symptoms as aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, irritability, etc.

Outcome measures

Outcome measures
Measure	Brivaracetam n=29 Participants The subjects will be treated with Brivaracetam (BRV) tablets 200 mg/day during 12 weeks: four 25 mg tablets, twice daily. Based on the Investigator's judgement, at any time, the dose can be decreased to BRV 150 mg/day, 100 mg/day, or 50 mg/day. Flexible dosing, can be up- and down-titrated as needed. At the end of the Treatment Period, the subject will either enter the N01372 long-term follow-up study or down-titrate during 4 weeks.
Number of Subjects Who Are Free From Nonpsychotic Behavioral Side Effects Over the Entire Treatment Period	3 subjects

SECONDARY outcome

Timeframe: From Study Entry (Visit1, Week -1) to the end of the Treatment Period (Visit 6, Week 12) or Early Discontinuation Visit

Population: The Safety Set (SS) consisted of all subjects who received at least 1 dose of Brivaracetam.

An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product that does not necessarily have a causal relationship with this treatment. A treatment emergent AE is any event that emerges during treatment having been absent pre-treatment, or worsens relative to the pre-treatment state.

Outcome measures

Outcome measures
Measure	Brivaracetam n=29 Participants The subjects will be treated with Brivaracetam (BRV) tablets 200 mg/day during 12 weeks: four 25 mg tablets, twice daily. Based on the Investigator's judgement, at any time, the dose can be decreased to BRV 150 mg/day, 100 mg/day, or 50 mg/day. Flexible dosing, can be up- and down-titrated as needed. At the end of the Treatment Period, the subject will either enter the N01372 long-term follow-up study or down-titrate during 4 weeks.
Incidence of Treatment Emergent Adverse Events During the Study Period	67 events

SECONDARY outcome

Timeframe: From Study Entry (Visit1, Week -1) to the end of the Treatment Period (Visit 6, Week 12) or Early Discontinuation Visit

Population: The Safety Set (SS) consisted of all subjects who received at least 1 dose of Brivaracetam.

An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product that does not necessarily have a causal relationship with this treatment.

Outcome measures

Outcome measures
Measure	Brivaracetam n=29 Participants The subjects will be treated with Brivaracetam (BRV) tablets 200 mg/day during 12 weeks: four 25 mg tablets, twice daily. Based on the Investigator's judgement, at any time, the dose can be decreased to BRV 150 mg/day, 100 mg/day, or 50 mg/day. Flexible dosing, can be up- and down-titrated as needed. At the end of the Treatment Period, the subject will either enter the N01372 long-term follow-up study or down-titrate during 4 weeks.
Withdrawal Due to an Adverse Event (AE) During the Study Period	2 subjects

SECONDARY outcome

Timeframe: From Study Entry (Visit1, Week -1) to the end of the Treatment Period (Visit 6, Week 12) or Early Discontinuation Visit

Population: The Safety Set (SS) consisted of all subjects who received at least 1 dose of Brivaracetam.

A serious adverse event is any untoward medical occurrences in a subject administered study treatment, whether or not the event is related to treatment, with at least one of the follow outcomes: death, life-threatening, initial inpatient hospitalization or prolongation of hospitalization, significant or persistent disability/incapacity, congenital anomaly/birth defect, or an important medical event that may jeopardize the subject and require a medical/surgical intervention.

Outcome measures

Outcome measures
Measure	Brivaracetam n=29 Participants The subjects will be treated with Brivaracetam (BRV) tablets 200 mg/day during 12 weeks: four 25 mg tablets, twice daily. Based on the Investigator's judgement, at any time, the dose can be decreased to BRV 150 mg/day, 100 mg/day, or 50 mg/day. Flexible dosing, can be up- and down-titrated as needed. At the end of the Treatment Period, the subject will either enter the N01372 long-term follow-up study or down-titrate during 4 weeks.
Occurrence of Serious Adverse Events During the Study Period	1 events

SECONDARY outcome

Timeframe: From 4 weeks prior to Visit 2 (Week 0) to the end of the Treatment Period (Visit 6, Week 12) or Early Discontinuation Visit

Population: The Efficacy Analysis Set (EAS) consisted of all subjects who received at least 1 dose of Brivaracetam and had at least 1 post-Baseline day of seizure daily record card (subject diary card).

The POS frequency is standardized to a 28-day duration and changes in POS frequency are measured relative to the reported seizure counts for the 4 weeks prior to Visit 2 (Week 0). Partial seizures can be classified into one of the following three groups: * Simple partial seizures (IA) * Complex partial seizures (IB) * Partial seizures evolving to secondarily generalized seizures (IC)

Outcome measures

Outcome measures
Measure	Brivaracetam n=15 Participants The subjects will be treated with Brivaracetam (BRV) tablets 200 mg/day during 12 weeks: four 25 mg tablets, twice daily. Based on the Investigator's judgement, at any time, the dose can be decreased to BRV 150 mg/day, 100 mg/day, or 50 mg/day. Flexible dosing, can be up- and down-titrated as needed. At the end of the Treatment Period, the subject will either enter the N01372 long-term follow-up study or down-titrate during 4 weeks.
Partial Onset Seizure (POS) Frequency Over the Treatment Period for Subjects With Focal Epilepsy	6.0 partial onset seizures Interval 2.2 to 17.7

SECONDARY outcome

Timeframe: From 4 weeks prior to Visit 2 (Week 0) to the end of the Treatment Period (Visit 6, Week 12) or Early Discontinuation Visit

Population: This variable was not analyzed and no results are available.

Generalized seizure days are standardized to a 28-day duration and changes in generalized seizure days are measured relative to the reported seizure counts for the 4 weeks prior to Visit 2 (Week 0). Generalized seizures (Type II) include the following seizure types: * Absence (IIA1) * Atypical absence (IIA2) * Myoclonic (IIB) * Clonic (IIC) * Tonic (IID) * Tonic-clonic (IIE) * Atonic (IIF) A specific effect of BRV on the occurrence of generalized seizures was not assessed.

Outcome measures

Outcome data not reported

Adverse Events

Brivaracetam

Serious events: 1 serious events

Other events: 13 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Brivaracetam n=29 participants at risk The subjects will be treated with Brivaracetam (BRV) tablets 200 mg/day during 12 weeks: four 25 mg tablets, twice daily. Based on the Investigator's judgement, at any time, the dose can be decreased to BRV 150 mg/day, 100 mg/day, or 50 mg/day. Flexible dosing, can be up- and down-titrated as needed. At the end of the Treatment Period, the subject will either enter the N01372 long-term follow-up study or down-titrate during 4 weeks.
Psychiatric disorders Suicidal ideation	3.4% 1/29 • Number of events 1 • Adverse Events were collected from Screening Period (Week -1) over the 12-weeks Treatment Period until the Safety Visit (Week 15-18 + max 7 days). Adverse Events refer to the Safety Set (SS) consisting of all subjects who received at least 1 dose of Brivaracetam.
Psychiatric disorders Suicide attempt	3.4% 1/29 • Number of events 1 • Adverse Events were collected from Screening Period (Week -1) over the 12-weeks Treatment Period until the Safety Visit (Week 15-18 + max 7 days). Adverse Events refer to the Safety Set (SS) consisting of all subjects who received at least 1 dose of Brivaracetam.

Other adverse events

Other adverse events
Measure	Brivaracetam n=29 participants at risk The subjects will be treated with Brivaracetam (BRV) tablets 200 mg/day during 12 weeks: four 25 mg tablets, twice daily. Based on the Investigator's judgement, at any time, the dose can be decreased to BRV 150 mg/day, 100 mg/day, or 50 mg/day. Flexible dosing, can be up- and down-titrated as needed. At the end of the Treatment Period, the subject will either enter the N01372 long-term follow-up study or down-titrate during 4 weeks.
Psychiatric disorders Insomnia	6.9% 2/29 • Number of events 2 • Adverse Events were collected from Screening Period (Week -1) over the 12-weeks Treatment Period until the Safety Visit (Week 15-18 + max 7 days). Adverse Events refer to the Safety Set (SS) consisting of all subjects who received at least 1 dose of Brivaracetam.
General disorders Fatigue	10.3% 3/29 • Number of events 3 • Adverse Events were collected from Screening Period (Week -1) over the 12-weeks Treatment Period until the Safety Visit (Week 15-18 + max 7 days). Adverse Events refer to the Safety Set (SS) consisting of all subjects who received at least 1 dose of Brivaracetam.
Infections and infestations Nasopharyngitis	6.9% 2/29 • Number of events 2 • Adverse Events were collected from Screening Period (Week -1) over the 12-weeks Treatment Period until the Safety Visit (Week 15-18 + max 7 days). Adverse Events refer to the Safety Set (SS) consisting of all subjects who received at least 1 dose of Brivaracetam.
Musculoskeletal and connective tissue disorders Back pain	10.3% 3/29 • Number of events 4 • Adverse Events were collected from Screening Period (Week -1) over the 12-weeks Treatment Period until the Safety Visit (Week 15-18 + max 7 days). Adverse Events refer to the Safety Set (SS) consisting of all subjects who received at least 1 dose of Brivaracetam.
Nervous system disorders Headache	17.2% 5/29 • Number of events 7 • Adverse Events were collected from Screening Period (Week -1) over the 12-weeks Treatment Period until the Safety Visit (Week 15-18 + max 7 days). Adverse Events refer to the Safety Set (SS) consisting of all subjects who received at least 1 dose of Brivaracetam.
Nervous system disorders Dizziness	6.9% 2/29 • Number of events 2 • Adverse Events were collected from Screening Period (Week -1) over the 12-weeks Treatment Period until the Safety Visit (Week 15-18 + max 7 days). Adverse Events refer to the Safety Set (SS) consisting of all subjects who received at least 1 dose of Brivaracetam.
Nervous system disorders Tremor	6.9% 2/29 • Number of events 2 • Adverse Events were collected from Screening Period (Week -1) over the 12-weeks Treatment Period until the Safety Visit (Week 15-18 + max 7 days). Adverse Events refer to the Safety Set (SS) consisting of all subjects who received at least 1 dose of Brivaracetam.
Psychiatric disorders Depression	6.9% 2/29 • Number of events 2 • Adverse Events were collected from Screening Period (Week -1) over the 12-weeks Treatment Period until the Safety Visit (Week 15-18 + max 7 days). Adverse Events refer to the Safety Set (SS) consisting of all subjects who received at least 1 dose of Brivaracetam.

Additional Information

UCB (Study Director)

UCB Clinical Trial Call Center

Phone: +1 887 822 9493

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: GT60